Species-dependent in vivo mRNA delivery and cellular responses to nanoparticles.
Marine Z C HatitMelissa P LokugamageCurtis N DobrowolskiKalina PaunovskaHuanzhen NiKun ZhaoDaryll VanoverJared P BeyersdorfHannah E PeckDavid LoughreyManaka SatoAna CristianPhilip J SantangeloJames E DahlmanPublished in: Nature nanotechnology (2022)
Nanoparticles are tested in mice and non-human primates before being selected for clinical trials. Yet the extent to which mRNA delivery, as well as the cellular response to mRNA drug delivery vehicles, is conserved across species in vivo is unknown. Using a species-independent DNA barcoding system, we have compared how 89 lipid nanoparticles deliver mRNA in mice with humanized livers, primatized livers and four controls: mice with 'murinized' livers as well as wild-type BL/6, Balb/C and NZB/BlNJ mice. We assessed whether functional delivery results in murine, non-human primate and human hepatocytes can be used to predict delivery in the other species in vivo. By analysing in vivo hepatocytes by RNA sequencing, we identified species-dependent responses to lipid nanoparticles, including mRNA translation and endocytosis. These data support an evidence-based approach to making small-animal preclinical nanoparticle studies more predictive, thereby accelerating the development of RNA therapies.
Keyphrases
- wild type
- endothelial cells
- high fat diet induced
- clinical trial
- drug delivery
- induced pluripotent stem cells
- binding protein
- pluripotent stem cells
- genetic diversity
- metabolic syndrome
- insulin resistance
- liver injury
- big data
- deep learning
- adipose tissue
- machine learning
- drug induced
- artificial intelligence
- walled carbon nanotubes
- circulating tumor
- cell free